Circadian control of kynurenine pathway enzymes in the rat pineal gland, liver, and heart and tissue- and enzyme-specific responses to lipopolysaccharide.

Amino acid tryptophan is catabolised via the kynurenine and serotonin-melatonin pathways, leading to various biologically active metabolites involved in regulating immunity, metabolism, and neuronal function. The levels of these metabolites are determined by the enzymes, which respond to altered homeostasis and pathological processes in the body. For the pineal gland, most work has centred on the serotonin-melatonin pathway. Still, no information exists on the expression of kynurenine pathway enzymes (KPEs), which may compete for the same substrate. Therefore, in this study, we investigated the physiological expression of KPEs in the rat pineal gland and their alterations in response to acute inflammation. We further compared the pineal expression profiles with the KPE expression in the rat liver and heart. Our data indicate the basal, non-induced expression of KPEs in the pineal gland, liver, and hearts, with a few first-step enzyme exceptions, such as Tdo and Ido1, and the first-step enzyme of serotonin pathway Tph1. This physiological expression was regulated in a circadian manner in the pineal gland and liver but not in the heart. Peripheral treatment with lipopolysaccharide resulted in mild upregulation of Tph1 in the pineal gland and heart, more robust upregulation of KPEs in the pineal gland and heart, but downregulation of Kmo, KatII, and Kynu in the liver. Altogether, our data provide evidence on the physiological expression of KPEs in the pineal gland, liver, and heart, which is regulated by the circadian clock in a tissue-specific manner. Furthermore, we show the temporal dynamics and bidirectional change in the transcriptional patterns of KPEs, Tph1, Per2, Nr1d1, and Stat3 in response to systemic administration of lipopolysaccharide in these tissues.

Constant Light in Critical Postnatal Days Affects Circadian Rhythms in Locomotion and Gene Expression in the Suprachiasmatic Nucleus, Retina, and Pineal Gland Later in Life.

The circadian clock regulates bodily rhythms by time cues that result from the integration of genetically encoded endogenous rhythms with external cycles, most potently with the light/dark cycle. Chronic exposure to constant light in adulthood disrupts circadian system function and can induce behavioral and physiological arrhythmicity with potential clinical consequences. Since the developing nervous system is particularly vulnerable to experiences during the critical period, we hypothesized that early-life circadian disruption would negatively impact the development of the circadian clock and its adult function. Newborn rats were subjected to a constant light of 16 lux from the day of birth through until postnatal day 20, and then they were housed in conditions of L12 h (16 lux): D12 h (darkness). The circadian period was measured by locomotor activity rhythm at postnatal day 60, and the rhythmic expressions of clock genes and tissue-specific genes were detected in the suprachiasmatic nuclei, retinas, and pineal glands at postnatal days 30 and 90. Our data show that early postnatal exposure to constant light leads to a prolonged endogenous period of locomotor activity rhythm and affects the rhythmic gene expression in all studied brain structures later in life.